Pectin penicillin preparation



July 15, 1952 H. WELCH PECTIN PENICILLIN PREPARATION Filed March 4, 1949 ff'l O Q O l JNVENToR. /5/2- Patented `uly 15, 1952 Henry Weich, silver spring,M., assigner muler v' United States of America,

Y I Application March 4, 1949 Serial N0. 79,624 y t iciaim. (c1. 1er-.65) f (Granted under the act of March, 3, 1883, as"

amended April 30, 1928; 370 0. G. 757) 'f My invention relates to a novel pectin penicillin preparation anda process for the production thereof.

This application is an improvement upon and in part a continuation of applications, Serial Number 752,298 filed June 3, 1947 for Therapeutic Products, now my Patent Number 2,491,537, and Serial Number 770,558 iiled August 25, 1947, for Pectin Products and the Process for Making Them, now my Patent Number 2,518,510.

The relatively long maintenance of vblood concentrations of penicillin following the injection of procaine penicillin'in oil containing aluminum monostearate has resulted in `a relatively low peak concentration. By peak concentration is lmeant the highest concentration of penicillin obtainable in the blood immediately following injection. The .peak concentration obtained with this drug following the injection of 300,000 units averages approximately 0.13 unit per milliliter. This l'l w.peak concentration is not satisfactory in thetreatment of acute diseases due to pencil- 1in sensitive bacteria. Clinicians vutilizing this product do not obtain the rapid dramatic cures which were obtainable with aqueous solutions of sodium or potassium penicillin. For example, acute pneumonias and severe streptococcic infactions do not show the dramatic response to the aluminum monostearate preparation containing procaine penicillin that has been obtainable in the past with aqueous penicillin'. Furthermore, in the treatment of syphilis, where the prolonged action of the aluminum monostearate preparation containing procaine penicillin should have its greatest value, the results obtained again are not asv satisfactory as have been obtainable with aqueous penicillin. VThe prolonged action of the aluminum monostearate preparation containing procainepenicillin results fromtwo factors, (l) the insolubility of the procaine penicillin,--andi (2)...the protective effect from solution in :body 'iiuids resulting ,fromV the presence of the'paluminum monostearate itself.V y monostearateis; a hydrophobic substance and lits water repel1encydelays, solution and absorption of the procaine penicillin.

not contain procfaine' penicillin but potassium penicillin instead, and the action of both of these penicillins was prolonged" inthe body because ofthe presence of aluminum monostearate. By actual trial' the addition of. 50,000

unitsof crystalline penicillin (potassium or sodium) to" thelst'andard monos tearate preparation increases' the peak level somewhat (on the orderl of 0.5 unit per milliliter of serum). This blood concentration (0.5 unit' per milliliter of serum) is quite loWpWhen comparedV With'the injection of 50,000 Yunits of crystalline penicillin alone. which resultsin a peak concentration of peni` cillin in the blood of'approximately 2.0 units per milliliter.

In the patent applicationslisted above (Serial Number 752,298 now my Patent Number 2,491,537,

and Serial Number 770,558, now my Patent Num-l ber 2,518,510) it wasdemonstrated that the injection of dry crystalline sodium or potassium penicillin in oil containing relatively large amountsY of pectin resulted in Va prolongation of penicillinfactivity in the body. It was observed oil) 'prolongation'of the action of penicillin Awas not obtained. Pec'tin itself isa hydrophilic agent and the'fprincipleof the original pectin in oil preparation described in, theabove identified apv plications' was related tothese hydrophilic'qual-k ities. Thus when penicillin in oil withpectinwas injected into the body the pectin attracted and withdrewrv Water from' the tissues; formed alv gel, and v.thus Vprotected the penicillinwithin theA gel matrix from rapid absorption bythe l'tissue viiuids.

Aluminum ...It maymeexpected .thatthe Vad'ditiont the aluminum. monostearate.procainezpenicillin prep4 f aration; of either potassium or sodium crystalline penicillin (both of which are `extremely soluble)l wouldfbefa satisfactorulmeans `of increasing the sofcalled, peakfl concentrations' However,

ici'llin 'froz'rrk rapid absorption by tisbutsini'ilarly protects any other penicil- Qing nant-afan .prepariiQnS/ intimmonostearatenotjonly protects pro-` j With' theknowledge that` aluminum monostearate' isa hydrophobic substanceand has a strong) wa' ter repellency 'and-j that pectin is a hydrophilicA substance j and thus' has a-f strongattraction', forwater, it; appearedy possible-that' these properties of aluminum vmor'iost'earate and-'pecti could be utilized in aproduct Athat would-give relatively high vpeak, levels -ofV penicillin in L ,the body. Such a product obviously could Inot" contain suiiicient pectin to form a gel since if it/did vthe result wouldbe the marked prolongation effect obtained and-described under vthe abovejpatent ap-Y plications (Serial Number 752,298 and Serial Number ,770,558)A IjIoWeyerl utilising .:veriy smalle iquanuties of pcctinproloagatibn effects.

sodium 'orf resolution of the material.

therefore, in the present invention, vcrystalline n potassium penicillin is coated with an extremely thin layer of pectin, moisture is eliminated by vacuum drying, and the pectin coated penicillin is then added to the basic procaine penicillin in oil containing 2 percent aluminum monostearate.

Details of the procedure used in making the preparation are as follows:

VTen grams of potassium penicillin (crystalline) Yare dissolved in 32 m1, of a 1.0'percent solutionof pectin (0.320 gm.). When dissolved, the penicillin-pectin solution is placed in a ,blender withthe blades `turning at slow speed. Approximately l750 m1. of acetone (moisture content0.5%` or less) is rapidly added (final acetone concen; tration for crystallization 95%) and the speed of the blender increased to full astlie crystals begin forming and allowed .to vrun ror 30-60 seconds.

The crystals are collected onpaper'by vacuum ltrationand immediately washed four times with pureac'tone. This is to remove4 residual wateras'rapidly asf possible and thus prevent The lter cake is dried in vacuo at 80-90 C. for four hours and. broken into a ne powder by rotating a few minutes in a sterile ball mill or bacterial grinder.' It i'sthen collected, sterilized by heat and preserved in a tightly stoppered bottle. The coated potassiumpenicillin microscopically consists ofA long slender needles. This procedure utilizes approximately 1 mg. of pectin for each 30 mg. (50,000 units) of penicillin.

The addition of acetone to the aqueous 4peni- Y cillinpectin solution results4 in a coprecipitation of penicillin and pectin. The precipitation'of the penicillin and pectin is almost simultaneous. The pectin precipitates out of solution in particles of approximately one micron'or less. 'The potassium penicillin precipitates aslong slender' needles which are coated .with the micron sized pectin Itis essential'to obtain. an eiicient precipitation of .penicillin and pectin that 4 The crystalline potassium penicillin used was the same salt as that employed in making the pectin treated material. The assay values of the nished product vwas 94%I of. that calculated for the copr'ecipitated salt, and 95% of the calculated value for the crystalline potassium salt.

' Twenty flve volunteers wereselected. Thirteen received the procaine penicillin in oil with aluminum4 monostearate containing the pectin coated'sa-lt and twelve received the procaine penicillin in oil containing the uncoated salt.

. Blcods. 'were' drawn at one, two and three hours and the serum penicillin level determined by the Bacillus subtilis serial dilution assay. The following, tables show the results obtained.

Pem'ofzzm mood levels following the infection of the pre'- Y cipitation be. practically simultaneous.v Adelay.

inthe precipitation rof the penicillin because of;` foneigample, excess water inthe acetone results in a productwhich is notv eicient, in lbringing waits/mg.V Seven. hundred milliliters of pooled Y procaine penicillin with aluminum'monostearate- Vingoil was kdivided:into'fiive equal lots/.4' One lot was-subdivided andheld as .f control. Four exe' perimental lots .were prepared` as followsz 4 A; Pooled procaine penicillinplus4.75 gms; oi'pol tassiumpenicillin. toY afford 50,0001units/ml. j `Yof*acidedcrystalline penicillin.- ControlV (no pectin). Bz' Pooled'proc'aine penicillinplus l4.75 gmsrof Y crystalline pectinx;v .Y Y CIL-Pooled procaine `"penicillinplus. 9.5 lgm s:.;of if "p'ota'ss'um'vfpenicillin, l'to afford. 100,000

' pectin.

'I units/inl.`V fof f'added crystallineapenicillin. Y l

' Y coatedpot-assium penicillin' herethe one ml. of procaine vpenicillin;uzith. alum?.imi/m monostea'mte in oil and50,000.1l1tits;aj-'notatie` sium. penicillin pectin coated Average Penicillin blood. levels following'theiniectonrof one ml. of procaine penicillin with. 'aluminuml 1 No blood.

Y times as highas a preparation'containing'OOO "potassium penicillin coatedwith units; of uncoated potassium penicillinat #the peak concentration.V A- graph showingthefre-` sultson the 25 patients testedisligure -1i of-the accompanyingdrawing.v 'Y

' Following the resultsl obtainedv withproca-ine penicillinV ijn 'oil'4 wirnialuminum monostearate: Y

300,000 bontainnig cloo'funits c centrationswere increased e over; that `cnt fiille''withthis! @ma ncoated'i'potassiuin preparation containing the Penicillin levels following the injection of v300,000

units of procaine penicillin in oil with aluminum monostearate containing 100,000 units crystalline `,potassiurz/n penicillin with. pectin the technician filling the pectin coated material lled vthirteen syringes While the technician filling the uncoated crystalline potassium penicillin in the aluminum monostearatev preparation was filling four. Furthermore, when the procaine penicillin in oilcontaining aluminum'monostearate lto which had been added 100,000 untsof necessary to use more than one injection site because of the poor syringeability of this prepara )f5 Hour l Hour 2 Hours 96 Hours B, 1.0 l1.0 1.0 .06. K. 2. 0 2. 0 2. 0 i 125 B. 1.0 2.0 2.0 0 f C, 1.0 2 0 4.0 .06 G. 1.o 1.o 2.0 .06 B. 4.0 4.0 4.0L 0 y J., 0.5 1.0 1.0 .125 B. 1. 0 l. 0 2.`0 .125 D. 0. 5 .0. 5.- 1.0 ...06 T. 1.0 1. 0 0. 5 0 C. 2.0 1.o 2.o o .1., 0.5 1.0 1.0 .125

Average 1. 3 1. 46 2. 0 0. 06

Penicillin levels following the iniectionfofy 300,000

units of procaine penicillin in oil .withA aluminum monostearate containing 100,000 units crystalline potassium penicillin Hour 1 Hour 2 Hours 96 Hours D. 1. 0 1.0 1. 0 06 C. 1.0 0. 5 1. 0 .125 B. 2. 0 1.0 1. 0 .06 A. 1.0 1.0 1.0 0 M. 0. 5 0. 5 0. 5 .06 M 0. 5 0.5 0. 5 06 B. 2. 0 2.0 2. O 0 S., 2. 0 2. 0 2. 0 0 W. 4.0 2. 0 2.0 .06 O. 1. 0 0. 5 0. 5 0 C. 2.0 4. 0 1. 0 0 S., 1.0 0. 5 0. 5 .06

Average l. 5 1.3 1.08 0. 04

Curves showing a comparison of the two preparations (100,000 units potassium penicillin pectin coated plus 300,000 units procaine penicillin, and 100,000 units potassium penicillin not coated plus 300,000 units procaine penicillin) are illustrated in Figure 2 of the accompanying drawing. In addition to the blood samples taken at vone-half hour, one hour and two hours, samples were also taken at 96 hours. A

Since blood levels of at least two units per ml. were demonstrated with this type of' preparation and in addition a marked prolongation is obtained, the possibilities for uses of such a product are considerable. Where delayed therapeutic retion.' ANo diculty was encountered when fthe potassium y penicillin coated with' 'pectin' was utilized at the 100,000units level inthe procaine in oil containing aluminum monostearate. l In othe words, the use of pectin coated potassium' peni; cillin vin vthe, aluminum monostearate' product improves the syringeability of the product. y

.In addition to the use of pectin coatedpenlcillin in the monostearate preparation, other ap plications are possible. When potassium penicillin .is coated with a `thin layer of pectin its physical characteristics are markedly changed. Potassium penicillin 'tends Ato cake in va container when the container is rapped sharply on a surface. When thecoated penicillin is s irln'ilarly treated Ythe caking does not occur because of the light uily characteristics of the product. Its use in inhalator administration is quite possible. Furthermore, the characteristics of the pectin coated penicillin should be of considerable value in filling *machines where potassium penicillin tends to cake up and result in inaccurate vial lling. f

To determine the peak level and prolongation, using procaine penicillin in oil with aluminum monostearate, 300,000 units, plus 100,000 units potassium penicillin (pectin coated) per ml. as a. possible single injection treatment for syphilis, ten volunteers were injected with 8-cc. (fi-cc. in each of two depots) of the above product. Each volunteer therefore received 2.4 million units of procaine penicillin and 800,000 units of potassium penicillin. Very high concentrations of penicillin in the blood were obtained in the first few hours after injection. The maximum level occurred at the second hour with an average level of 15.6 units per ml. of blood. This extremely high level resulted from levels obtained in two of the volunteers, B. and A., who showed.64.0' and,

32.0 units, respectively, in their blood at the second hour. Since all other patients but one showed levels of 8.0 units, it would appear that the average level is close to 8.0 units at the peak. Blood concentrations were determined not only during the first three hours but on the 5th, 6th, and `7th days as well. Eighty percent of the patients showed levels on the 5th day, 70 percent on the 6th day, While only one patient showed a level on the 7th day. One of the patients, B.. who showed no level on the 5th day, did have a level on the 6th day. It may be considered, therefore, that y percent of the patients injected iff haci` ignenicillinV in.: their Ablpcdiontheth day'. The hloodglevelslobtainedl.are.tabulated below..

mientas sacc, in; iwqdepots @fallecen/units v1mcaiiiepeiiiczilin. oiljwiti. aluminum' monostcanaie, piusjIOlLOiOO units, potassium penicil- Zinwcfiii'coaied) per mi. Toialj'zalv million o units-of Vz )rocaine penicilli'lijplus 800,000v units potassium penicillin Y vv15,1; the vrai Disease. Clinic inA the District Qi Co1umhia it has. bendemristratetdwith pencillin in oil and wax. that if patients can he;v

treated with thi'sjpreparationrsoasj to obtain a level in 90 percent of them for aperiodove days, a curev rate ofapproximatelyf) to 90 percent can be expected;Y Itwou'ld appear that the monostearate preparationVV containing pectincoated potassium penicillin can -accomplishthe above withf'ajsingle injection; Y This should-heextremely valuable'V in venerealdisease clinics,l

since high levels are obtained' with the product` V which should be satisfactory notonly for-ven.Y nereal diseases butv forv acute infectionsY as well` Theinvention described-herein may bemann-l facturedeand used anywhereby-or-for the- Government of -the- United States for governmental purposes. without the.; eyment to me! Q f.: any: royaltyihereenlnaccordance'withtherrOViSiQ ofthe actor. April 30J 1928,- (Ch. 460. 4,5, Stat., L:

IA claim-z y An.` i jeotablevpenlzcillin composition yielding; rapid high blood levels. with prolonged therapy'. levels of penicillir-iv whichA comprises procaine,

peniclllinrin oil with aluminummonostearate hav-ing con'lbineii therewith a water,-sol'ubleA V crystalline penicillin compounlcoated with about one-,partei pectin to about. tlrlirtvparts'offsafill` water-soluble penicillin compound, Awhereby 'theQl Number Name Date 1,928,346 Axelrod Sept, 26, 193.3 2,142,537 Tisza Jan. 3', 19,39,4 2,207,990V Miller June 16, 1940. 2,499,039 Libby Sept. 7, 1948. 2,491,537 Welch 9 Dec. 20, 1949.

OTHER REFERENCES Venei'ealDisease Infomation, February 1945, page 31.

Science News Letter, October 4, 1947, page 210.

American Druggist, July 1948, page 103.

J.Amer. Pharm. Assn., Practical Pharmacy- Ed., March 1949, page 179. 

